The insulin-like growth factor-I plays a role in most functions of the body. It is produced by the liver, released to the circulation, and utilized locally by most non-hepatic tissues. To study the roles of circulating versus paracrine effects of IGF-I, we gene-deleted the IGF-I from the liver using the cre/loxP system. Thess mice showed a marked reduction in circulating IGF-I but no obvious phenotype. When these mice were crossed with mice with an acid labile subunit gene-deletion, the circulating levels fell further. The crossed mice showed growth retardation and a reduction in bone density, suggesting an important role for circulating "endocrine" IGF-I. What remains to be determined are the roles for paracrine IGF-I. Liver IGF-I-deleted mice also showed a delayed onset of, and reduction in growth and metastases of an orthotopic colon cancer introduced by implanting the tumor onto the cecum. In a second model, DMBA-induced breast cancer and a genetically introduced breast cancer (SV40TAg mice) also delayed the appearance of tumors, reduced growth and number of tumors in the liver IGF-I-deleted mice. These results suggest that circulating IGF-I levels may be important in the risk for cancer growth and metastases.